Efficacy and Safety of Eplerenone for Treating Chronic Kidney Disease: A Meta-Analysis

Background In recent years, a large amount of clinical evidence and animal experiments have demonstrated the unique advantages of mineralocorticoid receptor antagonists (MRA) for treating chronic kidney disease (CKD). Aims Accordingly, the present study aimed to systematically assess the second-generation selective MRAs eplerenone's safety and effectiveness for treating CKD. Methods Four databases (PubMed, The Cochrane Library, Embase, and Web of Science) were searched for randomized controlled trials (RCT) correlated with eplerenone for treating CKD up to September 21, 2022. By complying with the inclusion and exclusion criteria, literature screening, and data extraction were conducted. Results A total of 19 randomized controlled articles involving 4501 cases were covered. As suggested from the meta-analysis, significant differences were reported with the 24-h urine protein (MD = −42.23, 95% confidence interval [CI] = -76.72 to −7.73, P = 0.02), urinary albumin-creatinine ratio (UACR) (MD = −23.57, 95% CI = −29.28 to −17.86, P < 0.00001), the systolic blood pressure (SBP) (MD = −2.73, 95% CI = −4.86 to −0.59, P = 0.01), and eGFR (MD = −1.56, 95% CI = −2.78 to −0.34, P = 0.01) in the subgroup of eplerenone vs placebo. The subgroups of eplerenone vs placebo (MD = 0.13, 95% CI = 0.07 to 0.18, P < 0.00001) and eplerenone vs thiazide diuretic (MD = 0.18, 95% CI = 0.13 to 0.23, P < 0.00001) showed the significantly increased potassium levels. However, no statistical significance was reported between the eplerenone treatment groups and the control in the effect exerted by serum creatinine (MD=0.03, 95% CI = −0.01 to 0.07, P = 0.12) and diastolic blood pressure (DBP) (MD = 0.11, 95% CI = −0.41 to 0.63, P = 0.68). Furthermore, significant risks of hyperkalemia were reported in the eplerenone group (K+ ≥ 5.5 mmol/l, RR = 1.70, 95%CI = 1.35 to 2.13, P=<0.00001; K+≥6.0 mmol/l, RR = 1.61, 95% CIs = 1.06 to 2.44, P = 0.02), respectively. Conclusions Eplerenone has beneficial effects on CKD by reducing urinary protein and the systolic blood pressure, but it also elevates the risk of hyperkalemia.


Introduction
CKD has become a globally recognized serious public health problem and a major factor contributing to the global burden of disease [1]. At present, the common drugs for CKD treatment consist of ACEI or AREB, which are capable of reducing urine protein and protecting the kidneys by blocking the renin-angiotensin-aldosterone system. SGLT-2i and GLP-1 analogues ofered unique renal protection in diabetic nephropathy as well. Besides, MRAs, acting on mineralocorticoid receptors and suppressing excessive MR activation, could be an efective supplementary treatment for the existing clinical treatment of CKD cases [2]. Tough several nonsteroidal MRAs achieving fewer side efects were developed and studied, they have not yet achieved extensive clinical applications. Eplerenone, the second-generation selective MRAs, should be considered a treatment for CKD [3,4]. Terefore, the clinical application value of CKD will be comprehensively analysed from the clinical indicators closely related to the prognosis of CKD.
Hence, we conducted this meta-analysis to systematically assess the second-generation selective MRAs eplerenone's safety and efectiveness for treating CKD.

Search Strategy.
Tis meta-analysis protocol was performed in strict accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements [5]. A total of 4 databases (PubMed, Te Cochrane Library, Embase, and Web of Science) were searched up to September 21, 2022. Te search terms covered "chronic kidney disease," "mineralocorticoid receptor antagonists," and "eplerenone."
(a) Adult male and nonpregnant female cases diagnosed with CKD (GFR > 30 ml/min/1.73 m 2 , serum potassium (K + ) ≤ 5.0 mmol/l in 24 h before randomization) [1]. (b) Study cases may or may not have had a history of mild to moderate hypertension (SBP/DBP ≥ 140/ 90 mmHg), whereas only SBP/DBP ≤ 180/ 110 mmHg and without symptomatic hypotension were eligible. (c) All articles were randomized controlled trials (RCTs) and crossover articles, assessing the efect of eplerenone with or without ACEI/ARB, in comparison with placebo or active control as a treatment for CKD for at least 4 weeks.

Exclusion Criteria.
(1) Duplicate published or incomplete literature; (2) meta-reviews, case reports, letters, meeting abstracts, etc.; (3) articles that cannot obtain the full text and the required outcome indicators; (4) nonhuman clinical trials and non-RCTs of eplerenone therapy; and (5) articles of CKD with an unclear diagnosis or combined with other diseases.

Study Selection and Data Extraction.
By complying with the inclusion and exclusion criteria, two authors screened the title and abstract of the respective literature, and read the full text of the literature that met the criteria. Lastly, the data were extracted independently. Any disagreement between the 2 authors was addressed by consensus or by a third investigator. Data collection consisted of frst authors, years and countries of literature, study designs, the No. of cases involved, interventions, study duration, as well as the endpoints of the study.

Evaluation of the Risk of Bias.
Evaluation of the risk of bias was performed by the two authors with the use of the Cochrane Collaboration's risk of bias evaluation kit, covering the following items: (1) selective report (report bias); (2) incomplete outcome information (attribution bias); (3) blinding of outcome evaluation (detection bias); (4) blinding of participants and personnel (performance bias); (5) allocation concealment (selection bias); (6) random sequence generation (selection bias); and (7) other biases.

Statistical Analysis.
Our study employed RevMan 5.3 software (the Cochrane Collaboration, UK) for this metaanalysis. With the use of the 95% confdence interval (CI) and mean diference (MD), the analysis was conducted on the continuous variable. Besides, the dichotomous variable had the expression of relative risk (RR) with a 95% CI. Te I 2 statistic was adopted for evaluating statistical heterogeneity, which was not considered to be signifcant when I 2 < 50% and P > 0.1, and fxed-efect model analyses were conducted for the data pooling; otherwise, the randomefect model was chosen. A sensitivity investigation was carried out for evaluating the individual trial's contribution to the pooled efect through the sequential omission of the respective trial. Te graphic data were presented through forest plots. And funnel plots were employed for testing publication biases.

Evaluation of Sensitivity Analysis and Publication Bias.
Sensitivity analysis of the involved articles showed no literature caused signifcant interference with the results of the meta-analysis, which meant the involved articles had good stability. Te funnel plots were systematically performed with the efectiveness and adverse events indicators, including 24-h proteinuria, UACR, systolic pressure, and eGFR. As indicated in Figure 8, the distribution of the (A) to (D) funnel plots was symmetrical, and the scatter points of the study were mostly within the scope of the funnel plots, thereby demonstrating that the possibility of publication bias was insignifcant.

Discussion
CKD results from diverse causes and is characterized by the progressive and irreversible loss of renal function, taking up about 11%-16% of the global population [25,26]. Numerous basic and animal articles have verifed that MRAs are capable of signifcantly suppressing the activity of proinfammatory cytokines and pro-oxidants, improving the antiinfammatory response of kidney tissue, improving renal ischemia, mitigating collagen deposition, and preventing renal fbrosis [2,27,28]. Clinical articles also clearly indicate that MRAs are efective in treating chronic kidney disease. In this paper, we found that eplerenone has benefcial efects on CKD by reducing urinary protein and the systolic blood pressure, but with the risk of hyperkalemia at higher doses. 6 International Journal of Hypertension Articles have suggested that renal proteinuria predicts the acceleration of the course of progressive renal insufciency and the shorter survival period of CKD cases [29]. Accordingly, reducing proteinuria can beneft the kidneys and reduce the risk of progression to ESRD [30,31]. As suggested by the existing research summary. Eplerenone alone or in combination with ACEI/ARB can further signifcantly reduce proteinuria in cases sufering CKD and increase creatinine clearance, independent of its antihypertensive efects [28]. In this meta-analysis, compared with the placebo control, eplerenone treatment improved the 24h urine protein and UACR levels of CKD cases, in line with the results of other existing articles [32]. However, this study revealed that no signifcant diference was reported in the efcacy of eplerenone treatment in comparison with the two controls of thiazide diuretic and RAS blockers in reducing urine protein. Tis fnding is explained below. First, existing clinical trials and treatment experience have confrmed the major mechanism and benefcial efects of RAAS inhibitors to reduce urine protein for kidney protection. Second, no signifcant diference was reported between eplerenone and thiazide diuretics in reducing urine protein in this metaanalysis. Relevant literature articles suggested that thiazide drugs have a certain degree of urinary protein-lowering efect [33,34], supporting the results of our study.
In this meta-analysis, the blood creatinine level of the eplerenone treatment group did not change signifcantly compared with the control group which is consistent with previous articles [35,36]. However, articles have suggested that a small number of cases experienced deterioration in renal function after the addition of eplerenone treatment in CKD cases [37]. In comparison with the placebo group, the eGFR of the treatment group was reduced, and there were statistical diferences, complying with the results of the above study. Considering that it is not correlated with the diferent baselines of the renal function of the subjects selected in the respective study, the renal function needs to be monitored in real time during the clinical application process. However, eGFR was more signifcantly reduced in the thiazide diuretic group, as compared with that of the eplerenone group. A prospective, multicentre clinical study (Cosmo-CKD) conducted in Japan demonstrated that, though hydrochlorothiazide can reduce urine protein and blood pressure [33], it reduces eGFR to a certain extent, complying with the results here. It is not considered to be correlated with increased aldosterone secondary to volume reduction [38].
In this meta-analysis, the efect of eplerenone on lowering SBP was better than that of the placebo group and weaker than that of the thiazide diuretic control and     International Journal of Hypertension presented no signifcant diference in lowering blood pressure in comparison with the CCBs group. Additionally, no signifcant diference was reported between the changes in DBP and the controls. Tis result is inconsistent with the fact that eplerenone has a signifcant antihypertensive efect on SBD and DBP, as stated in some research results [32,36]. Te reasons for the diference between the results of this study and other articles are described as follows. (1) Tiazide diuretic suppresses the reabsorption of sodium chloride within the proximal and distal renal tubules, and it directly lowers blood pressure. Its antihypertensive efect may be stronger than the weaker diuretic efect of mineralocorticoid receptor antagonists, and this only targets the distal renal tubules and collecting ducts. (2) Te comparison of the antihypertensive efcacy of eplerenone and CCBs is only involved in one study, with certain limitations. Tis can be clarifed by further high-quality RCT articles. (3) In this meta-analysis, DBP was not signifcantly diferent from the control, and the changes were not excluded, which was correlated with the good baseline blood pressure control of the respective involved study. In addition, there is no signifcant heterogeneity in a single subgroup in this metaanalysis, while the high total heterogeneity is considered to be correlated with the diference in antihypertensive efect attributed to diferent drug choices in the control. For adverse drug reactions, researchers (e.g., Sawai et al. [14], Ando et al. [15], Williams et al. [22], and Pitt et al. [23]) elucidated the drug treatment-related side efects during the treatment and the follow-up, thereby demonstrating the occurrence of no signifcant severe adverse reactions. El Mokadem et al. [11] also revealed that it is not common to discontinue medication as impacted by side efects in the respective treatment group. In this meta-analysis, only statistical analysis of changes in serum potassium levels was performed, and the risk of hyperkalemia during Eplerenone treatment was discussed. Compared with the control, eplerenone increased serum potassium levels, which was statistically signifcant from the clinical perspective. Te risk      International Journal of Hypertension of hyperkalemia fell to two levels of ≥5.5 mmol/l and ≥6.0 mmol/l for statistics. In the hyperkalemia risk (≥5.5 mmol/l) group, in comparison with the placebo, eplerenone treatment was accompanied by hyperkalemia risk. No signifcant diference was reported in other subgroups, complying with the results of some articles [32,36,37], demonstrating that MRAs may be associated with the risk of hyperkalemia. Tere are also articles verifying that there is no signifcant risk of high potassium in eplerenone treatment [39]. Te reasons for the diferences in the research results are analysed as follows. From one perspective, it is considered to be correlated with the increased risk of high potassium with the combined application of ACEI/ARB drugs in the involved articles. Moreover, the diferences in the baseline blood potassium levels and baseline renal function of the populations involved in diferent articles are not excluded, and the risk of hyperkalemia is signifcantly increased in cases sufering high baseline blood potassium levels and poor renal function [40]. From another perspective, some articles have diferent defnitions of the threshold of hyperkalemia risk (some are defned as ≥5.5 mmol/l, and some articles are defned as 6.0 mmol/l). However, eplerenone treatment is associated with the risk of hyperkalemia compared with the RAS blockers control. Tis is considered to be associated with the high-dose eplerenone treatment (100-200 mg) in the two selected articles in this treatment subgroup. Lastly, this research has the following shortcomings. (1) For the quality exhibited by the involved articles, the sample size of some involved articles was low, and some research     Figure 7: (a) Incidence of hyperkalemia (≥5.5 mmol/l) in articles comparing eplerenone to placebo/active control. (b) Incidence of hyperkalemia (≥6.0 mmol/l) in articles comparing eplerenone to placebo/active control. Te black diamond represents summary data with the center of the estimate pooled with the risk ratio, and the width covers the corresponding 95% CIs.

Conclusion
In brief, this study suggested that eplerenone is capable of efectively lowering protein excretion in CKD cases and that it impacts blood pressure, with the blood creatinine kept stable during the treatment. But it can, to a certain extent, upregulate the blood potassium level and elevate the risk of hyperkalemia. So we need to screen the renal function and blood potassium level before treatment and formulate the drug treatment dose by complying with the principle of individualization. Tus, eplerenone can act as an efective supplement to the existing clinical treatment of cases suffering chronic kidney disease, but its long-term clinical efcacy and safety need to be further confrmed.

Data Availability
Te clinical data of the population used to support the fndings of this study are available from the corresponding author upon request.

Conflicts of Interest
Te authors declare that there are no conficts of interest in this manuscript.

Authors' Contributions
Honglei Hu and Mengdie Cao contributed equally to this manuscript.

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International Journal of Hypertension